Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 19, Pages 5655-5664Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv279
Keywords
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Funding
- Italian Ministry of Health [RF2010, RC2008]
- NIH [DC02281]
- Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]
- Academy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146, 69818, 251723, 263729]
- Haigh Fellowship in age-related deafness
- Deafness Research UK [444:UEI:SD]
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02, 076113/B/04/Z, 079895]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Human Genome Research Institute (NHGRI)
- National Institute of Child Health and Human Development (NICHD)
- Juvenile Diabetes Research Foundation International (JDRF)
- Juvenile Diabetes Research Foundation International
- Wellcome Trust
- National Institute for Health Research Cambridge Biomedical Research Centre
- European Commission [018996]
- French Ministry of Research
- [U01 DK062418]
- MRC [G0000934, G1001799, MR/N01104X/1] Funding Source: UKRI
- Medical Research Council [G1001799, MR/N01104X/1, G0000934] Funding Source: researchfish
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Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium-and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.
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